Any references cited herein are incorporated by reference.
Targeted molecular medicine is an exciting research approach, aimed at developing safer and more effective drugs and treatment therapies. The structural protein tubulin is an appealing target for such investigations, as it is already known to interact with some of the most successful chemotherapy drugs, including the taxanes, Vinca alkaloids, epothilones, and dolastatins (Bai R. et al., Biochem Pharmacol. 1990; 39:1941-9; Schiff P. B. et al., Nature, 1979:277:665-7; Owellen R. J. et al., Biochem Biophys. Res. Commun. 1972; 47:685-91; and Bollag D. M. et al., Cancer Res. 1995:55:2325-33). Unfortunately, while many of these drugs are clinically invaluable, many can affect cancerous and non-cancerous cells indiscriminately. It is this nature of many chemotherapy agents that results in the undesirable side-effects associated with these treatments.
The lack of specificity currently poses one of the greatest challenges in cancer chemotherapy. However, the expression of several β-tubulin isotypes provides a unique platform on which to develop drugs with increased specificity for only those isotypes expressed principally in cancerous cells (Lu Q. et al., J. Biol. Chem. 1994; 269:2041-7; Luduena R. F., Int. Rev. Cytol. 1998; 178:207-75; and Roach M. C. et al., Cell Motil. Cytoskeleton, 1998; 39:273-85). The currently available anti-tubulin drugs appear to bind to multiple β-tubulin isotypes, showing limited preference for one over another (Khan I. A. et al., Invest. New Drugs. 2003; 21:3-13; Banerjee A. et al., J. Biol Chem. 1992; 267:13335-9; Schwarz P. M. Drug Development Research. 2002; 55:91-6; Luduena R. F. et al., Biochem. 1995; 34:15751-9). For example, vinblastine seemingly binds with greater affinity to the βII-tubulin isotype (Khan I. A. et al., Invest. New Drugs. 2003; 21:3-13), while expression of the βIII-tubulin isotype has been correlated with resistance to anti-tubulin agents (Katsetos C. D. et al., J. Child Neurol. 2003; 18:851-66: discussion 867). A precise explanation for isotype expression has yet to be posited. However, it is evident that cancerous cells express a wide range of tubulin isotypes, not simply those present in the cells from which they are derived (Katsetos C. D. et al., Arch. Pathol. Lab Med. 2000:124:535-44; and Scott C. A., et al., Arch Otolaryngol Head Neck Surg. 1990; 116:583-9). A chemotherapy drug selected to target a tubulin isotype expressed in cancer cells could potentially minimize or eliminate damage to non-cancerous cells.
Several structures of anti-cancer drug-tubulin complexes have now been crystallographically determined and the mechanisms of anti-mitotic action of the drugs postulated (Ravelli R. B. et al., Nature. 2004; 428:198-202; Gigant B. et al., Nature. 2005; 435:519-22; Nogales E. et al., Nature. 1995; 375:424-7). Colchicine has extremely strong anti-mitotic activity, that is only observed at toxic or near toxic levels which limits its use as a cancer treatment.
Colchicine has been widely used in immune-mediated diseases, and beneficial effects were reported in the treatment of psoriatic arthritis (P. Seidemann, B. Fjellner, A. Johannesson, J. Rheumatol. 14 (1987) 777-779) and leukocyte-cytoclastic vasculitis (J. P. Callen, J. Am. Acad. Dermatol. 13 (1987)193-200). Moreover, recent studies have showed that colchicine inhibits leukocyte-endothelial cell adhesion (S. J. Rosenman, A. A. Ganji, W. M. Gallatin, F.A.S.E.B. J. 5 (1991)1603-1609) and T cell activation (Y. A. Mekory, D. Baram, A. Goldberg, A. Klajman, Cell. Immunol. 120 (1989) 330-340) by binding to intracellular tubulin monomers, which prevents their polymerization (G. O. Borisy, E. W. Taylor, J. Cell. Biol. 34 (1967) 533-548). Thus, colchicine has the potential to impair the process of antigen recognition and may inhibit the cancer cell growth. However, antimitotic colchicine is used only in research due to its toxicity.
The effects associated with the pharmacological profile of colchicine and the frequent occurrence of drug resistance has prompted the search for compounds that are comparable to colchicine's activity and more suitable for cancer treatment.